Xanthin derivative and process of making same.



UNITED STATES Patented August 9, 190 4.

PATENT OEEIcE.

MITFORD O. MASSIE, OF WASHINGTON, DISTRICT OF COLUMBIA, ADMINIS- TRATOR OF FRITZ AOH, DECEASED, ASSIGNOR TO O. F. BOEHRINGER & SOEHNE, OF MANNHEIM-l/VALDHOF, GERMANY, A FIRM.

XANTHIN DERIVATIVE AND PROCESS OF MAKING SAME.

SPECIFICATION forming part of Letters Patent No. 767,352, dated August 9, 1904.

Application filed May 6, 1903. Serial No. 155,961. (Specimens) I T to whom, it may concern:

Be it known that FRITZ AoH, deceased, late a citizen of Germany, and a resident of Mannheim, Germany, did invent new and useful Im- 5 provements in the Preparation of Xanthin Derivatives and I, MI'IFoRD O. MAssIE, a citizen of the United States, and a resident of WVa-shington, in the District of Columbia, the dulyconstitutedadministrator of the estate of said FRITZ AoH, deceased, do hereby declare the following to be a full, clear, and exact description of the said invention of said decedent, such as will enable others skilled in the art to which it appertains to make and use the same.

The present invention relatesto the preparation of xanthin derivatives, and in particular the preparation of xanthin carboxylic acids, their salts, and esters.

In application Serial No. 142,590, filed February 7, 1903, said Fritz Ach described a method of splitting off the methyl group in the position 8 in 8-methyl xanthins, said method consisting in preparing an 8-trichloromethyl xanthin and then submitting it to hydrolysis. A further study and investigation of this reaction has developed the fact that the hydrolysis of trichloromethyl xanthin proceeds in two steps or phases, carboxylic acid. being formed as an intermediate product as the result of the first step, according to the equation,

l R o I oo C-N 4 I ll o.oooH.

RN-CN where R denotes an alkyl radical. The carboxylic acids are finally during the second phase of the reaction converted into the corresponding Xanthin. Now it was further found by said inventor that these Xanthin carboxylic acids, which acids, as well as their salts and ester, are of considerable importance as therapeutic agents, may be obtained as final products from trichloromethyl xanthins. The inventor found three specific methods of proceeding from these trichloromethyl Xanthins to these carboxylic acids, all of which methods are generically characterized by the fact that they consist in substituting OOOR or the carboxyl group OOOH for the group C013 in the position 8 of the trichloromethyl Xanthin. One method consists in briefly boiling the trichloromethyl compounds with water and another in heating, them with a solution of an alkali salt of a weak acid such, for example, as acetate of potassiur n whereby the potassium salt of the xanthin carboxylic acid is formed. The third method devised by the inventor consists in heating the trichloromethyl compound with an alcohol, from which method the corresponding ester of the xanthin carboxylic acid results, which ester will yield the acid by saponification.

'By this new method of preparation the class of xanthin carboxylic acid, of which hitherto only one representative-viz., the caffein carboxylic acid-has been described, (by Gomberg in American Chemical Journal, Vol. XVII, page 4:12,) can be manufactured, and thus a number of new compounds embraced in this class are placed within the reach of the manufacturing chemist.

The present invention therefore consists generically in substituting a carboxyl group (OOOH or, more generically, OOOR where R denotes H, a metal, or an alkyl-radical) for the trichloromethyl group (CGla) in the position 80f an 8-trichloromethyl Xanthin.

The invention also consists in such further methods, features, and steps as will be hereinafter described,and pointed out in the claims.

A detailed description of this invention as embodied in a number of examples, forming what -is considered the preferred manner of carrying the same into practice, will now be given. The proportions given are all in weight unless otherwise stated.

Eamon/p10 1.Prepamt i0n of ammy Z {Ii/677 ?fim'v 2 cc 2 bow [71c (will from, 3-?)166/1 1 l- St'ri0/LZO/'0- 'nmt/ty l, aim/thin 741 hgl rl roly sz's.-One part of 3 methyl 8 trichloromethyl xanthin is dissolved in two hundred and forty parts of boiling water. Heat is developed, and, after cooling, 3-methyl xanthin carboxylic acid crystallizes outin the form of shining leaflets or folia. The acid may be recrystallized from about two hundred and fifty parts of hot Water at a temperature of substantially 100 centigrade, and only after a sustained boiling of such solution will carbonic acid be split off and liberated from the same. The above crystals contain two molecules of water of crystallization, which Water of crystallization is driven off with concurrent liberation of carbon dioxid if the crystals are heated to a temperature of substantially 120 centigrade. The ethyl ester of this new acid melts at 304 to 305 centigrade and the methyl ester at 270 centigrade. Both esters are soluble only with difficulty in alcohol. The new acid has the structural formula H N-CO I CH3 OC ON l I C. COOH CH3. NCN

Errmnple Q.Prqmrazfii0n 0f crtfl'en cmbomylic acirlfrmn 8-69ic/tZOromet/tyl ccqfl'eia.- Ten parts of the trichloro compound of 8-methyl caffein are boiled together With a solution of thirteen parts of acetate of potassium (corresponding to about four molecules) in one hundred and seventy parts of Water. It is found that good results are obtained by adding thirty parts of alcohol to the acetate of potassium solution before boiling. After a short time (about twenty-five minutes) the trichloro compound goes into solution, whereupon the liquid is concentrated somewhat by heating on the water-bath. After cooling the potassium salt of the cafi'ein carboxylic acid or caffein carboxylate of potassium is precipitated in the form of small snow-white aeicular crystals. In order to obtain the free acid, an aqueous solution of the potassium salt is acidulated with a mineral acid, whereby the caifein carboxylie acid is thrown out. The acid so produced is id entical with the compound described by (iomberg in American Chemical Journal, Vol. XVII, page L12, (at seq.

.lilcmny) Ze Preparation/1f theobromin carboa' lz'c acid from 8-zfrrichlowmwthg l theobromin.Two parts of trichloro-methyl theobromin are dissolved in sixty parts of ethyl alcohol and boiled with reflux i. 0., in a refluxcooler. After about one-half of an hour the separation of the ethyl ester of the new acid begins. The boiling is thereafter continued for a further period of two and one-half hours, whereupon the whole is allowed to cool. After cooling, the ester which has been precipitated is separated by filtration. The ester is thus obtained in a perfectly pure condition. The reaction by which the ester is formed takes place according to the equation l I OH; CO G-N l CFO (fi N CH3. NC N The new body, theobromin carboxylic acid ethyl ester, is soluble with difiiculty in water and alcohol, about five hundred parts of boiling alcohol being needed to dissolve one part of the ester. From such a solution the ester crystallizes in the form of felted needles having a melting-point of about 300 centigrade. By saponifying with alkali the acid can be obtained from the ester, an example of such saponification being the following: One part of the ethyl ester of the theobromin carboxylic acid is introduced into four parts, by volume, of double normal potash lye (double normal solution of KHO) having the temperature of the water-bath. The ester is thus completely 9 5 dissolved. The solution is then digested for a short time (two minutes) and then aeidulated with acetic acid to weak-acid reaction, whereby the potassium salt of the new acid is immediately precipitated. For purifying the same it is dissolved in warm water, centigrade,) of which it requires thirteen parts, and recrystallized from such solution. Under these conditions it precipitates slowly in the form of fine needles, such precipitation being rendered more complete by the addition of some alcohol, (about eight parts.) The free theobromin carboxylic acid may be obtained from an aqueous solution of this potassium salt by acidulating such solution with a mineral acid. it then crystallizes out in the form of smallpointed needle having a melting-point of 34:5 centigrade.

Theobromin carboxylic acid is difficultl y soluble in water and almost insoluble in alcohol, chloroform, and acetic ether. Its formula is HN-CO l l CH3 CO C-N All the examples given have the fact in common that under them the 8-trichloromethyl xanthin is treated with a reagent capable of substituting a carboxyl group for the chloromethyl radical C(Jls in the position 8.

The carboxyl group may be introduced either alone, as in Example 1 above, or con1- l QClZHSOH bined with a metal or an alkyl radical, thus I 3 producing a salt or an ester, as in Examples 2 and 3. The methods of and reagents for the introduction of the carboxyl group, as

employed'in Examples 1 and 2, are the subples that when an alkali salt of a Xanthin car boxylic acid is to be obtained a bath, specifically a solution, of an alkali salt of a weak acid is caused to react on the corresponding trichloromethyl xanthin, and if an ester is to be obtained the corresponding trichloromethyl Xanthin is heated with an alcohol or, more specifically, dissolved in an alcohol and heated until the ester is formed. The ester so formed may be converted into the corresponding alkali salt by saponifying the same in alkali-bath, preferably a solution.

hat is claimed, and desired to be secured by Letters Patent of the United States, is

1. The process of preparing an 8-Xanthin carboxylic acid, which consists in reacting upon an 8-trichloromethyl Xanthin with an agent which. substitutes the carboXyl group for the trichloromethyl radical in trichloromethyl Xanthin.

2. The process of preparing an S-Xanthin carboxylic acid which consists in heating an S-trichloromethyl Xanthin with an agent which replaces the trichloromethyl group in the trichloromethyl Xanthin with a carboXyl group.

3. The process which consists in heating trichloromethyl theobromin with an alcohol.

4. The process which consists in heating trichloromethyl theobromin with ethyl alcohol.

5; The process which consists in dissolving trichloromethyl theobromin in ethyl alcohol and heating until the ethyl ester of theobromin carboxylic acid is formed.

6. The process which consists in sapon'ifying theobromin carboxylic ethyl ester with alkali.

7. The process which consists in saponifying theobromin carboxylic ethyl ester in an alkali-bath until dissolved, and then acidifying the solution to weak-acid reaction to precipitate the corresponding alkali-salt.

8. The process which consists in saponifying theobromin carboXylic ethyl ester in an alkali-bath until dissolvechthen acidifying the solution to weak-acid reaction to precipitate the corresponding alkali salt, then separating and making an aqueous solution of the alkali salt, and acidulating the solution with mineral acid, whereby the corresponding carboxylic acid is precipitated.

9. The process which consists in heating trichloromethyl theobromin with an alcohol, separating the ester thus formed, and saponifying the same with alkali.

10. The process which consists in heating trichloromethyl theobromin with an ethyl alcohol, separating theester thus formed, and

saponilt'ying the same with alkali.

11. The process which consistsin dissolving trichloromethyl theobromin in ethyl alcohol and heating until the ethyl ester of theobromin carboxylic acid is formed, separating the ester thus formed, and saponifying the same with alkali.

12. The process which consists in heating trichloromethyl theobromin with an alcohol, separating the ester thus formed, saponifying the same with alkali until dissolved and acidifying the solution to weak-acid reaction to precipitate the alkali salt of the theobromin carboxylic acid.

13. The process which consists in heating trichloromethyl theobromin with an ethyl alcohol, separating the ester thus formed, saponifying the same with alkali until dissolved, and acidifying the solution to weak-acid reaction to precipitate the alkali salt of the theobromin carboxylic acid.

14:. The process which consists in dissolving trichloromethyl theobromin in ethyl alcohol and heating until the ethyl ester of theobromin carboxylic acid is formed, separating the ester thus formed, and saponifying the same with alkali.

15. The process which consists in heating trichloromethyl theobromin with an alcohol, separating the ester thus formed, saponifying the same with alkali until dissolved and acidifying the solution to weak-acid reaction to precipitate the alkali salt of the theobromin carboxylic acid, and, finally, separating and making an aqueous solution of the alkali salt and acidulating the solution with mineral acid, whereby the corresponding carboxylic acid is separated.

16. The process which consists in heating trichloromethyl theobromin with an ethyl alcohol, separating the ester thus formed, saponifying the same with alkali until dissolved, and acidifying the solution to weak-acid reaction to precipitate the alkali salt of the theobromin carboxylicacid, and, finally, separating and making an aqueous solution of the alkali salt, and acidulating the solution with mineral acid, whereby the corresponding carboXylic acid is separated.

17 The process which consists in dissolving trichlorotheobromin in ethyl alcohol and heatlng until the ethyl ester of theobromin carboxylic acid is formed, separating the ester IIO 18. As a new chemical compound, theobro- In testimony whereof I affix my signaturein min carboxylic acicl, having the structural forthe presence of tWo Witnesses. mulahereinbetfore given, which crystallizes in MITFORD C. MASSIE, the form of small pointed needles having a Administrator 0f the estate of A071 da- 5 melting-point of about 345 centigracle and ceased.

Which is soluble With difficulty in Water and Witnesses: almost insoluble in alcohol, chloroform and HELEN M. HUToI-IINGs,

acetic other. WALTER F. MOGINN. 

